Profiles of HCV core protein and viremia in chronic Hepatitis C: possible protective role of core antigen in liver damage

Carabaich, Alessandro; Ruvoletto, Mariagrazia; Bernardinello, Elisabetta; Tono, Natascia; Cavalletto, Luisa; Chemello, Liliana; Gatta, Angelo; Pontisso, Patrizia

doi:10.1002/jmv.20322

Cited by 14 publications

(12 citation statements)

References 22 publications

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“…22 Some evidence suggests that the ratio of HCV RNA to core antigen has prognostic value. 22,30 For the comparison of pre-LT samples to all post-LT samples, there was a nonsignificant trend toward a decrease in the ratio of HCV RNA to core antigen (14,000 vs. 8,000; P ϭ .34). The difference in the ratio was statistically sig- Fig.…”

Section: Early Viral Kineticsmentioning

confidence: 98%

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

et al. 2005

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This study tested the hypothesis that hepatitis C virus (HCV) RNA and core antigen levels rise more rapidly after liver transplantation (LT) in recipients of grafts from living donors (LD) versus deceased donors (DD). Eleven consecutive LD and 15 DD recipients were followed prospectively. Before LT, median HCV RNA levels were similar: 5.42 (LDLT) and 5.07 (DDLT) log 10 IU/mL (P ‫؍‬ NS). During the first 7 hours after LT a trend toward a greater HCV RNA decrease in LDLT patients was seen, although they received fewer blood replacement products during surgery. HCV RNA levels rose more rapidly in LDLT patients between days 1 and 3 (P ‫؍‬ .0059) and were higher in this group on days 2, 3, 4, and 5. Core antigen levels were significantly higher in LDLT patients on days 3 and 5, although they were similar before LT (P ‫؍‬ NS). Alanine aminotransferase (ALT) values were higher among LDLT patients from 8 to 14 days and from 4 to 24 months. Two-year graft and patient survival were 73% for LDLT patients and 80% for DDLT patients (P ‫؍‬ NS). In conclusion, viral load rose more rapidly in LD recipients and reached higher levels shortly after surgery. Greater ALT elevations were evident in the LDLT group, but survival rates were similar. The trend toward a greater initial viral load decrease in patients with LD grafts and the significantly sharper increase suggest that the liver plays a predominant role in both HCV clearance and replication. ( A fter transplantation of hepatitis C virus (HCV) patients, viral infection of the graft is nearly universal, providing a unique opportunity to examine interactions between the human liver and HCV. Grafts from living donors (LDs) differ from grafts from deceased donors (DDs) in characteristics such as the rapid increase in volume that occurs in LD grafts during the first week after surgery. 1 Several studies have compared outcomes of LD liver transplantation (LDLT) and DDLT in HCV patients. [2][3][4][5][6][7][8][9][10][11] Results have been inconsistent, in part, because of differences in experimental design and small sample sizes. 12-17 Concerning survival, no short-term difference was observed in a study of 65 DD versus 35 LD patients, 6 and analysis of the United Network for Organ Sharing liver transplant database showed that the 2-year survival of 279 LD and 3,955 DD recipients was virtually identical. 5 Other analyses of the same database, however, showed that graft survival was lower in LD recipients. 4,8 Studies of biopsy specimens have yielded conflicting results regarding the severity of recurrent hepatitis and the rate of progressive graft injury. 7,10,11 HCV may interact differently with LD grafts than with DD grafts, and this difference may lead to greater LD graft injury. Exceptionally high HCV RNA levels in the early postoperative period are associated with greater long-term liver damage in DDLT patients, 18,19 and a similar association may exist in LDLT patients. The popula-

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Section: Early Viral Kineticsmentioning

confidence: 98%

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

et al. 2005

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“…It has been proposed that infectious particles are assembled when genomic RNA-containing core particles bud through the endoplasmic reticulum (ER) membrane (47), acquiring the viral envelope and surface glycoproteins (14,15,48). However, it is currently unknown how the viral particles are transported from the ER through the secretory pathway.In infected individuals, HCV particles circulate as low-density lipoprotein (LDL)-virus complexes (3) characterized by very-low-to-low buoyant densities (from Ͻ1.03 to 1.25 g/ml), depending on the stage of the infection at which the sample is obtained (12,46). These LDL-virus particles are rich in triglycerides and contain HCV RNA, core protein, and apolipoproteins B and E (apoB and apoE) (3), which are components of the beta-lipoproteins (very-low-density lipoproteins [VLDL] and LDL) (11).…”

mentioning

confidence: 99%

“…In infected individuals, HCV particles circulate as low-density lipoprotein (LDL)-virus complexes (3) characterized by very-low-to-low buoyant densities (from Ͻ1.03 to 1.25 g/ml), depending on the stage of the infection at which the sample is obtained (12,46). These LDL-virus particles are rich in triglycerides and contain HCV RNA, core protein, and apolipoproteins B and E (apoB and apoE) (3), which are components of the beta-lipoproteins (very-low-density lipoproteins [VLDL] and LDL) (11).…”

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confidence: 99%

Cellular Determinants of Hepatitis C Virus Assembly, Maturation, Degradation, and Secretion

Gastaminza

Cheng

Wieland

et al. 2008

J Virol

404

452

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Intracellular infectious hepatitis C virus (HCV) particles display a distinctly higher buoyant density than do secreted virus particles, suggesting that the characteristic low density of extracellular HCV particles is acquired during viral egress. We took advantage of this difference to examine the determinants of assembly, maturation, degradation, and egress of infectious HCV particles. The results demonstrate that HCV assembly and maturation occur in the endoplasmic reticulum (ER) and post-ER compartments, respectively, and that both depend on microsomal transfer protein and apolipoprotein B, in a manner that parallels the formation of very-low-density lipoproteins (VLDL). In addition, they illustrate that only low-density particles are efficiently secreted and that immature particles are actively degraded, in a proteasome-independent manner, in a post-ER compartment of the cell. These results suggest that by coopting the VLDL assembly, maturation, degradation, and secretory machinery of the cell, HCV acquires its hepatocyte tropism and, by mimicry, its tendency to persist.Hepatitis C virus (HCV) establishes persistent infection in Ͼ70% of infected individuals (25), and over 170 million people are persistently infected worldwide. Persistent HCV infection is associated with a chronic inflammatory disease (hepatitis) that ultimately leads to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (25). Chronic infection is also associated with disorders of lipid metabolism (54), with abnormal accumulation of lipids in the liver parenchymal cells (steatosis) and reduced serum beta-lipoprotein levels (52). Currently, the only approved antiviral therapy for HCV is the administration of type I interferon combined with ribavirin. However, this therapy is toxic and is effective in only a fraction of cases (43).HCV is the sole member of the genus Hepacivirus, which belongs to the Flaviviridae family. The virus is enveloped, and the single-stranded positive-strand RNA genome contains a single open reading frame flanked by untranslated regions (5Ј UTR and 3Ј UTR) that contain RNA sequences essential for RNA translation and replication (17,18). Translation of the single open reading frame is driven by an internal ribosomal entry site (IRES) sequence present within the 5Ј UTR (24), and the resulting polyprotein, of approximately 3,000 amino acids in length, is processed by cellular and viral proteases into its individual components (44). The nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B are sufficient to support efficient HCV RNA replication in membranous compartments in the cytosol (10,35,39). Overexpression of the core, E1, and E2 proteins is sufficient for the formation of virus-like structures in insect cells (6), and expression of the viral polyprotein leads to the formation of virus-like particles in HeLa (38) and Huh-7 (23) cells. It has been proposed that infectious particles are assembled when genomic RNA-containing core particles bud through the endoplasmic reticulum (ER) membrane (47), acquiring the v...

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“…HCV RNA displays various density profiles, depending on the stage of the infection at which the sample is obtained (11,58). The differences in densities and infectivities have been attributed to the presence of host lipoproteins and antibodies bound to the circulating viral particles (24,58).…”

mentioning

confidence: 99%

Ultrastructural and Biophysical Characterization of Hepatitis C Virus Particles Produced in Cell Culture

Gastaminza

Dryden

Boyd

et al. 2010

J Virol

181

151

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We analyzed the biochemical and ultrastructural properties of hepatitis C virus (HCV) particles produced in cell culture. Negative-stain electron microscopy revealed that the particles were spherical (ϳ40-to 75-nm diameter) and pleomorphic and that some of them contain HCV E2 protein and apolipoprotein E on their surfaces. Electron cryomicroscopy revealed two major particle populations of ϳ60 and ϳ45 nm in diameter. The ϳ60-nm particles were characterized by a membrane bilayer (presumably an envelope) that is spatially separated from an internal structure (presumably a capsid), and they were enriched in fractions that displayed a high infectivity-to-HCV RNA ratio. The ϳ45-nm particles lacked a membrane bilayer and displayed a higher buoyant density and a lower infectivity-to-HCV RNA ratio. We also observed a minor population of very-lowdensity, >100-nm-diameter vesicular particles that resemble exosomes. This study provides low-resolution ultrastructural information of particle populations displaying differential biophysical properties and specific infectivity. Correlative analysis of the abundance of the different particle populations with infectivity, HCV RNA, and viral antigens suggests that infectious particles are likely to be present in the large ϳ60-nm HCV particle populations displaying a visible bilayer. Our study constitutes an initial approach toward understanding the structural characteristics of infectious HCV particles.

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Profiles of HCV core protein and viremia in chronic Hepatitis C: possible protective role of core antigen in liver damage

Cited by 14 publications

References 22 publications

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

Cellular Determinants of Hepatitis C Virus Assembly, Maturation, Degradation, and Secretion

Ultrastructural and Biophysical Characterization of Hepatitis C Virus Particles Produced in Cell Culture

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